Serum Levels of Apoptosis Inhibitor

RESEARCH ARTI CLE Open Access
Serum levels of apoptosis inhibitor of

macrophage are associated with hepatic fibrosis
in patients with chronic hepatitis C
Kumiko Mera
1
, Hirofumi Uto
1*
, Seiichi Mawatari
1
, Akio Ido
1
, Yozo Yoshimine
1
, Tsuyoshi Nosaki
1
, Kohei Oda
1
,
Kazuaki Tabu
1
, Kotaro Kumagai
1
, Tsutomu Tamai
1
, Akihiro Moriuchi
1
, Makoto Oketani
1
, Yuko Shimada
2
,
Masaaki Hidaka
3
, Susumu Eguchi
3
and Hirohito Tsubouchi
4
Abstract
Background: Apoptosis inhibitor of macrophage (AIM) and adipocytokines are involved in the metabolic
syndrome, which has been putatively associated with the progression of chronic hepatitis C (CHC). However, the
association between these cytokines and CHC is not fully elucidated. The aim of this study is to test whether serum
levels of AIM and adipocytokines are associated with histological features, homeostasis model assessment-insulin
resistance index (HOMA-IR), or whole body insulin sensitivity index (WBISI) in CHC patients.
Methods: Serum samples were obtained from 77 patients with biopsy-proven CHC. In 39 patients without overt
diabetes mellitus, a 75 g oral glucose tolerance test (OGTT) was performed and HOMA-IR and WBISI were
calculated.
Results: A serum AIM level of 1.2 g/ml was independently associated with advanced hepatic fibrosis (F2 or F3)
(odds ratio [OR], 5.612; 95% confidence interval [CI], 1.10328.563; P = 0.038) based on a multivariate analysis, but
there was no significant association between AIM and hepatic steatosis or inflammation. Furthermore, a serum
leptin level of 8.6 ng/ml was independently associated with the presence of hepatic steatosis (5%) (OR, 6.195;
95% CI, 1.40927.240; P = 0.016), but not hepatic fibrosis or inflammation. No relationship was observed between
levels of adiponectin or resistin and hepatic histological parameters based on a multivariate analysis. Although
serum levels of leptin, resistin, and adiponectin were significantly correlated with HOMA-IR and WBISI, there was no
significant relationship between serum AIM levels and HOMA-IR or WBISI, respectively.
Conclusion: High serum levels of AIM in CHC patients are potentially related to advanced hepatic fibrosis. AIM and
adipocytokines are possibly associated with pathological changes via a different mechanism.
Keywords: Apoptosis inhibitor of macrophage, Adipocytokine, Hepatic fibrosis, Hepatitis C virus, Chronic hepatitis,
Insulin resistance
Background
Chronic hepatitis C virus (HCV) infection is one of the
main causes of chronic liver disease. Host factors such
as obesity, insulin resistance (IR), and hepatic steatosis
have been reported to contribute to the progression
from chronic hepatitis C (CHC) to liver cirrhosis and
hepatocellular carcinoma (HCC) [1-3]. In addition,
chronic HCV infection contributes to the development
of hepatic steatosis and IR [4]. Hepatic steatosis and IR
have a significant impact on the acceleration of liver in-
jury and hepatic fibrosis in patients with CHC. Further-
more, the pathogenesis of steatosis and IR depend on the
viral genotype: increased steatosis has been linked to
HCV genotypes 2 and 3 [5,6], and body mass index
(BMI) and homeostasis model assessment of IR (HOMA-
IR) directly contribute to steatosis in patients infected
with HCV genotype 1 [5]. IR is also independently
* Correspondence: hirouto@m2.kufm.kagoshima-u.ac.jp
1
Digestive and Lifestyle Diseases, Department of Human and Environmental
Sciences, Kagoshima University Graduate School of Medical and Dental
Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan
Full list of author information is available at the end of the article
2014 Mera et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain
Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article,
unless otherwise stated.
Mera et al. BMC Gastroenterology 2014, 14:27
http://www.biomedcentral.com/1471-230X/14/27
associated with genotypes 1 and 4 [6]. The mechanisms
of these interactions, however, are not fully understood.
Apoptosis inhibitor of macrophage (AIM) was initially
identified as an apoptosis inhibitor that supports the sur-
vival of macrophages against various apoptosis-inducing
stimuli [7]. Recently, it has been reported that an in-
crease in the blood levels of AIM is a critical event in
the initiation of macrophage recruitment into adipose
tissue, which is followed by IR [8]. Miyazaki et al. sug-
gested that AIM is involved in the progression of meta-
bolic syndrome, including obesity and IR, in both an
advancing and inhibitory fashion [9], but the impact of
AIM on the pathogenesis of HCV-related chronic liver
disease has not been investigated.
Adipose tissue, skeletal muscle, and the liver are the
major insulin-sensitive organs in the human body. Adi-
pogenesis is the process by which preadipocytes differen-
tiate into adipocytes, which is induced by insulin.
Adipose tissuederived cytokines, so-called adipocyto-
kines, theoretically play an important role in the devel-
opment of IR [10]. The more familiar adipocytokines
include leptin, adiponectin, and resistin. Leptin is a pro-
inflammatory cytokine that accelerates the progression
of hepatic fibrosis and exacerbates the inflammatory
process in the liver [11]. In contrast, adiponectin reduces
hepatic fibrosis and exerts a hepatoprotective effect [12].
Further, resistin, a signaling molecule secreted from adi-
pocytes and monocytes, is known to be involved in in-
flammatory processes [13], and has recently been
reported to be associated with hepatic fibrosis [14,15].
However, their role in HCV-related chronic liver disease
is somewhat confusing and the results of various studies
have been contradictory [16-18].
In this study, we analyzed the association between
serum levels of AIM, leptin, adiponectin, and resistin,
and clarified the clinical significance of serum AIM
levels in patients with CHC. We then determined
whether serum levels of AIM are associated with histo-
logical features such as the degree of hepatic steatosis
and hepatic inflammation and the stage of hepatic fibro-
sis. In addition, we determined whether serum levels of
AIM and adipocytokines are associated with IR or sensi-
tivity in patients with CHC.
Methods
Patients
Seventy-seven consecutive patients with chronic liver dis-
ease due to HCV infection admitted to Kagoshima Uni-
versity Medical and Dental Hospital between February
2007 and July 2011 were analyzed in this retrospective
study. Ultrasound-guided liver biopsy was performed to
confirm the diagnosis. Patients were excluded from this
study if they met the following criteria: positive for hepa-
titis B surface antigen or a history of other types of
hepatitis, including autoimmune hepatitis and alcoholic
liver disease, or malignancies including HCC. An exist-
ence of HCC was confirmed by ultrasonography, com-
puted tomography, or both in patients with chronic
hepatitis. Blood samples were obtained just before
ultrasound-guided liver biopsy. Informed consent was
obtained from all patients. This study was approved by
the ethics committees of Kagoshima University Medical
and Dental Hospital.
Laboratory markers
We determined clinical laboratory parameters, such as
platelet count, and levels of albumin (Alb), total biliru-
bin, alanine aminotransferase (ALT), -glutamyl trans-
peptidase (-GTP), and -fetoprotein. Diabetes was
defined as fasting plasma glucose 126 mg/dL or pa-
tients treated with oral hypoglycemic medication or in-
sulin. Hemoglobin A1c (HbA1c) level was calculated as
a ratio of HbA1c to the total hemoglobin using chroma-
tography according to the Japan Diabetes Society (JDS)
method. Among 60 CHC patients without overt dia-
betes, including patients treated with oral hypoglycemic
medication or insulin, a 75 g oral glucose tolerance test
(OGTT) was performed in 39 patients. Serum insulin
levels were determined by radioimmunoassay. IR was
calculated by the homeostasis model (homeostasis model
assessment-insulin resistance, HOMA-IR) using the fol-
lowing formula: HOMA-IR = fasting insulin (U/ml)
plasma glucose (mg/dl)/405. The whole body insulin
sensitivity index (WBISI) was calculated using the fol-
lowing formula: WBISI = 10,000/square root of [fasting
glucose fasting insulin] [mean glucose mean insulin
during OGTT] [19]. WBISI, which is simple to calculate
and provides a reasonable approximation of whole-body
insulin sensitivity from OGTT values, is highly corre-
lated with the rate of whole-body glucose disposal dur-
ing euglycemic insulin clamping [19]. The HCV serotype
or genotype was determined with a serological genotyp-
ing assay kit (Immunocheck F-HCV Grouping; Inter-
national Reagents Co., Tokyo, Japan) or the HCV Core
Genotype kit (SRL Inc., Tokyo, Japan), respectively.
HCV genotype 1b was included with serotype I, and ge-
notypes 2a and 2b were included with serotype II. No
other HCV genotypes were detected in this study popu-
lation. HCV RNA titers were quantified by the Cobas
TaqMan PCR assay (Roche, Tokyo, Japan). Patients were
considered to have a high viral load if their titers were 5
log IU/mL or higher.
Serum AIM, adiponectin, leptin, and resistin levels
Serum was obtained by centrifuging the blood sample at
4000 g for 5 min at room temperature and then frozen
at 80C until further use. Serum AIM levels were mea-
sured in duplicate using the CircuLex Human AIM/
Mera et al. BMC Gastroenterology 2014, 14:27 Page 2 of 10
CD5L/Sp ELISA kit (CycLex Co., Ltd. Nagoya, Japan).
Serum leptin, adiponectin, and resistin levels were mea-
sured in duplicate using an enzyme-linked immunoassay
(Quantikine ELISA; R&D Systems, Minneapolis, MN).
Histopathology
Liver biopsy specimens were scored semiquantitatively
based on the New Inuyama classification by 3 experi-
enced hepatologists (SM, KT and KO) that were blinded
to clinical data [20]. Fibrosis was scored as F0, no fibro-
sis; F1, portal fibrous widening; F2, portal fibrous widen-
ing with bridging fibrosis; F3, bridging fibrosis plus
lobular distortion; or F4, probable or definite cirrhosis.
Inflammation was graded as A0, none to minimal; A1,
mild; A2, moderate; or A3, severe. Hepatic steatosis was
evaluated based on the percentage of hepatocytes con-
taining cytoplasmic vacuoles, and the degree of hepatic
steatosis was classified as absent (<5%) or present (5%),
according to a previous study [21].
Statistical analysis
Results are expressed as means standard deviation
(SD). P values less than 0.05 were considered statistically
significant. Statistical analyses were performed using
Chi-square or MannWhitney U test, as appropriate.
Correlation coefficients were calculated by Spearmans
rank correlation analysis. The discriminatory power for
each putative marker was described using the receiver
operating characteristics (ROC) area under the curve
(AUC) (ROC-AUC). Multivariate analyses were per-
formed using logistic regression. Multivariate logistic re-
gression was used to calculate odds ratios (ORs) and
95% confidence intervals (95% CIs) while simultaneously
controlling for potential confounders. Cut-off values
were obtained from ROC-AUC analysis. Statistical ana-
lysis was conducted using PASW Statistics 18 (SPSS
Inc., Chicago, IL).
Results
Characteristics of patients with biopsy-proven chronic
hepatitis
Table 1 summarizes the baseline clinical parameters of all
77 HCV-infected patients who received ultrasound-guided
liver biopsy to confirm the diagnosis. The mean age was
56.1 12.4 years (range, 2076 years) and mean BMI was
23.5 2.9 kg/m
2
(range, 16.432.2 kg/m
2
). Forty-seven pa-
tients were infected with serotype I and the remaining 30
patients with serotype II. Complete histological data, in-
cluding fibrosis stage, inflammation score, and steatosis
grade was available for all patients. Fibrosis was absent in
3 patients (3.8%), F1 in 33 (42.9%), F2 in 24 (30.3%), and
F3 in 17 (21.5%). As a result, there were no F4 patients
among the 77 HCV-infected patients. Hepatic steatosis
was present in 18 patients, and absent in 59 patients.
Association between serum AIM levels and other
laboratory data in patients with chronic hepatitis C
Among the laboratory parameters listed in Table 2,
serum AIM levels were positively correlated with ALT
and hyaluronic acid. Serum AIM levels were negatively
correlated with platelet count, total cholesterol, and al-
bumin, suggesting that serum AIM levels are potentially
associated with hepatic fibrosis and hepatic reserve.
Diagnostic value of serum AIM levels for advanced
hepatic fibrosis
Platelet count and serum levels of hyaluronic acid are
known diagnostic markers of hepatic fibrosis. To evaluate
the ability of AIM to diagnose advanced hepatic fibrosis
Table 1 Baseline clinical, demographic, histologic and
metabolic characteristics of 77 patients with chronic
hepatitis C
Patients (number) 77
Age (years) 56.1 12.4
Sex [male/female] 31/46
Body mass index (kg/m
2
) 23.5 2.9
Male (kg/m
2
) 23.8 2.9
Female (kg/m
2
) 23.3 3.1
HCV serotype [I/II] 47/30
Viral load of HCV (log IU/ml) 5.9 1.1
Platelet count (10
4
/l) 18.1 7.2
Total cholesterol (mg/dl) 170.7 38.6
Albumin (g/dl) 4.3 0.4
ALT (IU/l) 64.5 53.9
-GTP (IU/l) 50.1 62.2
Diabetes [absent/present] 60/17
Hemoglobin A1c (%) 5.4 0.6 (n = 75)
Fasting plasma glucose (mg/dl) 97.0 22.1
Fasting insulin (U/ml) 9.8 5.7 (n = 40)
HOMA-IR 2.2 1.5 (n = 40)
Leptin (ng/ml) 7.6 5.1
Adiponectin (ng/ml) 9.0 6.2
Resistin (ng/ml) 8.5 4.6
AIM (g/ml) 1.39 0.86
Hyaluronic acid (ng/ml) 95.9 114.0 (n = 75)
-fetoprotein (ng/ml) 7.1 11.2
Histologic characteristics
Activity [A0-1/2-3] 32/45
Fibrosis [F0-1/2-3] 36/41
Steatosis [<5%/5%] 59/18
Data are shown as the means standard deviations or number.
HCV, hepatitis C virus; ALT, alanine aminotransferase; -GTP, -glutamyl
transpeptidase; HOMA-IR, homeostasis model assessment-insulin resistance;
AIM, apoptosis inhibitor of macrophage.
(F23), we examined AIM in addition to hepatic fibrosis
markers. In an AUC-ROC analysis, hyaluronic acid was the
strongest diagnostic marker for advanced fibrosis (AUC-
ROC, 0.854), and the AUC-ROCs for platelet count and
AIM were 0.769 and 0.764, respectively. In addition, AUC-
ROC analysis revealed that a serum AIM level of 1.2 g/ml
was the optimal cut-off value to differentiate between ab-
sent or mild hepatic fibrosis (F01) and advanced hepatic
fibrosis, with 73.2% sensitivity and 75.0% specificity.
Factors associated with the severity of hepatic fibrosis
Table 3 shows the demographic, clinical, and biochemical
characteristics of patients with advanced fibrosis (F23)
versus absent or mild fibrosis (F01). Univariate analysis
revealed that age, platelet count, albumin, ALT, -GTP,
AIM, and hyaluronic acid were significantly associated
with advanced hepatic fibrosis. In contrast, serum leptin,
adiponectin, and resistin were not associated with ad-
vanced hepatic fibrosis. In a multivariate regression model
including age (55 years), platelet count (<17 10
4
/l), al-
bumin (<4.4 g/dl), ALT (43 IU/l), -GTP (27 IU/l), AIM
(1.2 g/ml), and hyaluronic acid (40 ng/ml), advanced
hepatic fibrosis was independently associated with ALT,
AIM, and hyaluronic acid (Table 4).
Factors associated with the severity of hepatic steatosis
and inflammation
The relationship between serum levels of AIM or adipo-
kines and the severity of histological features including
hepatic steatosis and inflammation were assessed in CHC
patients. Serum albumin, -GTP, leptin, resistin, and hya-
luronic acid, as well as the presence of diabetes, were asso-
ciated with hepatic steatosis (5%) in the univariate
analysis (Table 5). Based on multivariate regression analysis
that included albumin (4.0 g/dl), -GTP (44 IU/L), leptin
(8.6 ng/ml), resistin (8.8 ng/ml), hyaluronic acid
(76.4 ng/ml), presence of diabetes, and age (55 years),
leptin was independently associated with hepatic steatosis
(Table 6). Furthermore, in the univariate analysis, age,
platelet count, and serum levels of albumin, ALT, -GTP,
AIM, and hyaluronic acid were associated with more se-
vere hepatic inflammation (A23, Table 7), but there
were no statistically significant association between these
parameters and hepatic inflammation in a multivariate
regression model including age (55 years), platelet count
(<17 10
4
/l), albumin (<4.4 g/dl), ALT (43 IU/L), -
GTP (27 IU/L), AIM (1.2 g/ml), and hyaluronic acid
(45.4 ng/ml) (all P >0.1 in multivariate analysis).
Association between serum levels of AIM and IR in
patients with chronic hepatitis C
Among 77 CHC patients who underwent liver biopsy, 39
patients without overt diabetes mellitus were available for
the OGTT. In these 39 patients, there was no significant
association between serum levels of AIM and adiponectin,
leptin, or resistin. Serum levels of AIM tended to be corre-
lated with HOMA-IR, but this association did not show
statistical significance (Figure 1, r = 0.269, P = 0.098). Fur-
thermore, serum levels of leptin and resistin were posi-
tively correlated with HOMA-IR, and serum levels of
adiponectin were negatively correlated with HOMA-IR
(Figure 1). In addition, serum levels of adiponectin, leptin,
and resistin were significantly associated with WBISI, but
serum levels of AIM were not correlated with WBISI
(Figure 2, r = 0.130, P = 0.430).
Discussion
HCV infection is the most important cause of chronic
hepatitis, liver cirrhosis, and HCC. The incidence of
HCC increases with increasing severity of hepatic fibro-
sis in patients with HCV infection. Hepatic inflamma-
tion and steatosis are thought to affect the progression
of hepatic fibrosis. In addition, IR and obesity are
thought to be associated with histopathology of the liver.
Several adipocytokines and macrophage-derived mole-
cules are reported to be associated with IR and obesity;
we examined the association between these molecules
and histopathological features in the liver. In this study,
we demonstrated that serum AIM levels in patients with
CHC were positively associated with hepatic fibrosis, but
leptin, adiponectin, or resistin levels did not show this
association. In contrast, serum levels of adiponectin, lep-
tin and resistin were associated with IR, but AIM was
Table 2 Association between serum levels of apoptosis
inhibitor of macrophage and clinical parameters in
patients with chronic hepatitis C
Factor Number Correlation coefficient P value*
Age 77 0.085 0.463
Body mass index 77 0.074 0.521
Viral load of HCV 77 0.152 0.188
Platelet count 77 0.374 0.001
Total cholesterol 77 0.325 0.004
Albumin 77 0.309 0.006
ALT 77 0.253 0.027
-GTP 77 0.222 0.052
Hemoglobin A1c 75 0.069 0.559
Fasting plasma glucose 77 0.075 0.517
Leptin 77 0.039 0.740
Adiponectin 77 0.029 0.800
Resistin 77 0.034 0.771
Hyaluronic acid 75 0.330 0.004
-fetoprotein 77 0.008 0.942
*Calculated by Spearmans rank correlation analysis.
ALT, alanine aminotransferase; GTP, -glutamyl transpeptidase; HOMA-IR,
homeostasis model assessment-insulin resistance.
not. Although the pathophysiological mechanism of
AIM in CHC patients remains unclear, our study is the
first to illustrate the clinical significance of AIM in pa-
tients with CHC.
In this study, we showed that serum AIM levels as deter-
mined by ELISA were higher in CHC patients with severe
hepatic fibrosis compared to those with no or mild hepatic
fibrosis. In addition, we confirmed that six HCV-infected
cirrhotic patients who underwent liver transplantation had
serum AIM levels greater than 1.2 g/ml (data not shown).
Gangadharan et al. previously reported that serum levels of
the AIM protein were elevated in hepatitis C patients with
liver cirrhosis compared to healthy controls, using a prote-
omics method based on 2-dimensional gel electrophoresis
(2-DE) [22]. They speculated that the increased serum
AIM levels observed in cirrhotic patients may be associ-
ated with HCV infection rather than cirrhosis. However,
serum AIM levels determined by proteomics using 2-DE
analysis were previously reported to reflect the severity of
hepatic fibrosis in nonalcoholic fatty liver disease [23].
ALT 43 IU/l was more strongly associated with advanced
hepatic fibrosis compared to AIM levels 1.2 g/ml in our
study; this may suggest that any association is indeed
weak, but it is well known that ALT levels in patients with
liver cirrhosis are lower than levels in patients with
chronic hepatitis. Further, ALT <43 IU/L was observed in
half of the patients with HCV-associated liver cirrhosis
who received liver transplantation (data not shown).
Therefore, the serum concentration of AIM is potentially
a marker of hepatic fibrosis in chronic liver disease. Fur-
ther validation studies involving patients with chronic liver
disease, including those with HCV-associated liver cirrho-
sis, chronic hepatitis B, autoimmune liver disease, and
fatty liver disease, are needed.
Table 4 Multiple logistic regression analysis for factors
associated with advanced hepatic fibrosis in patients
with chronic hepatitis C
Variable Odds ratio 95% confidential
interval
P value
Age (55 years) 1.025 0.168-6.253 0.979
Platelet count (<17 10
4
/l) 5.617 0.933-33.826 0.060
Albumin (<4.4 g/dl) 2.236 0.470-10.638 0.312
ALT (43 IU/l) 5.906 1.179-29.589 0.031
-GTP (27 IU/l) 2.447 0.489-12.247 0.276
AIM (1.2 g/ml) 5.612 1.103-28.563 0.038
Hyaluronic acid (40 ng/ml) 11.617 2.233-60.443 0.004
ALT, alanine aminotransferase; -GTP, -glutamyl transpeptidase;
AIM, apoptosis inhibitor of macrophage.
Table 3 Comparison of the clinical characteristics of chronic hepatitis C patients with (F23) or without (F01)
advanced hepatic fibrosis
F0 F1 F2 F3
(n = 36) (n = 41)
Factor Mean or number Maximum Minimum Mean or number Maximum Minimum P value
*
Age (years) 53 71 22 59 76 20 0.029
Sex (male/female) 14/22 17/24 0.818
2
) 23.2 30.1 16.4 23.6 32.2 17.8 0.814
HCV serotype (I/II) 21/15 26/15 0.815
Viral load (log IU/ml) 6 7.3 2.7 5.8 7.3 2.4 0.606
Platelet count (10
4
/l) 21 41.9 9.8 15.5 39.7 5.4 <0.001
Total cholesterol (mg/dl) 179.4 295 84 163 251 92 0.071
Albumin (g/dl) 4.5 5.1 3.5 4.1 4.9 2.9 <0.001
ALT (IU/L) 40.3 181 13 85.8 244 17 <0.001
-GTP (IU/L) 31.7 114 12 66.3 468 12 0.001
Diabetes (absent/present) 6/30 11/30 0.283
Fasting plasma glucose (mg/dl) 95.3 155 75 98.6 196 72 0.810
Hemoglobin A1c (%) 5.3 (n = 35) 6.7 4.6 5.5 (n = 40) 7.6 4.6 0.861
Leptin (ng/ml) 6.9 21.8 1.0 8.2 21.3 1.1 0.086
Adiponectin (ng/ml) 8.8 27.3 1.7 9.1 26.7 1.1 0.653
Resistin (ng/ml) 8.1 27.6 2.5 8.9 17.8 3 0.156
AIM (g/ml) 1.06 2.02 0.41 1.68 6.44 0.76 <0.001
Hyaluronic acid (ng/ml) 42.6 10.0 292.7 145.0 (n = 39) 10.0 636.0 <0.001
*Calculated by Chi-square test for categorical variables or MannWhitney U test for continuous variables.
ALT, alanine aminotransferase; -GTP, -glutamyl transpeptidase; HOMA-IR, homeostasis model assessment-insulin resistance; AIM, apoptosis inhibitor of macrophage.
AIM is a member of the scavenger receptor cysteine-
rich superfamily that was initially identified as an inhibitor
of apoptosis that supports the survival of macrophages
against different types of pro-apoptotic stimuli [5]. It is re-
portedly solely produced by tissue macrophages, including
Kupffer cells [24,25]. In addition, we observed that mRNA
expression of AIM in the human hepatic stellate cell line
LI90 was weak, but it was strong in the human macro-
phage cell line THP-1 (data not shown). Which cell types
express AIM in chronic liver disease was not determined
in this study; Kupffer cells should be the main source of
AIM in liver with hepatic fibrosis. Kupffer cells are
resident macrophages of the liver. Activated Kupffer cells
play a pivotal role in triggering and maintaining inflamma-
tion in chronic liver disease including CHC and nonalco-
holic steatohepatitis (NASH) [26,27]. Persistent hepatic
inflammation and hepatic stellate cell resistance to apop-
tosis are some of the mechanisms involved in progressive
hepatic fibrogenesis [28]. AIM induced by Kupffer cells
may contribute to these mechanisms, and we speculate
that elevated serum AIM levels may be due to increased
production in vivo. However, our study was cross-
sectional, and a longitudinal study involving a larger
number of patients with an even distribution among the
different stages of fibrosis is needed to elucidate the
causal relationship between AIM and hepatic fibrosis. In
addition, the association between serum AIM levels and
hepatic reserve or renal function should be closely
examined.
IR is independently associated with the severity of fi-
brosis in chronic liver disease, including CHC and
NASH [29,30]. In addition, patients may have advanced
hepatic fibrosis complicated by IR, abnormal glucose
metabolism, or diabetes mellitus [31]. IR is thought to
directly activate profibrogenic signaling pathways
[32,33]. However, the molecular mechanisms through
which IR influences hepatic fibrosis are not fully eluci-
dated. Recently, it was reported that the whole-body glu-
cose intolerance and IR observed in obese AIM wild-
type mice were less severe in obese AIM knockout mice,
Table 5 Comparison of the clinical characteristics of chronic hepatitis C patients with or without hepatic steatosis (5%)
Steatosis (<5%) Steatosis (5%)
n = 59 n = 18
*
Age (years) 55.2 76 20 59.1 69 33 0.257
Sex (male/female) 26/33 5/13 0.217
2
) 22.3 30.1 16.4 23.8 32.2 19.9 0.800
Platelet count (10
4
/l) 18.3 41.9 7.4 17.1 36.2 5.4 0.434
Total cholesterol (mg/dl) 171.4 295 84 168.4 222 114 0.814
Albumin (g/dl) 4.3 5.1 3.3 4.0 4.9 2.9 0.023
ALT (IU/l) 63.1 244 13 69.1 191 20 0.125
-GTP (IU/l) 40.6 239 12 81.4 468 12 0.010
Hemoglobin A1c (%) 5.3 (n = 57) 7.6 4.6 5.6 7.1 4.7 0.084
Leptin (ng/ml) 7.0 21.8 1.0 9.6 17.3 3.5 0.006
Adiponectin (ng/ml) 9.3 27.3 1.1 8 26.1 1.7 0.493
Resistin (ng/ml) 8.1 27.6 2.5 9.9 17.5 4 0.042
AIM (g/ml) 1.37 4.56 0.41 1.43 6.44 0.72 0.290
Hyaluronic acid (ng/ml) 71.9 (n = 57) 292.7 10 171.6 636.0 11.2 0.021
ALT, alanine aminotransferase; GTP, -glutamyl transpeptidase; HOMA-IR, homeostasis model assessment-insulin resistance; AIM, apoptosis inhibitor of macrophage.
Table 6 Multiple logistic regression analysis for factors
associated with hepatic steatosis (5%) in patients with
chronic hepatitis C
Variable Odds ratio 95% confidential
interval
P value
Age (55 years) 4.839 0.788-29.733 0.089
Albumin (<4.0 g/dl) 1.771 0.310-10.099 0.520
-GTP (44 IU/L) 3.077 0.741-12.783 0.122
Diabetes mellitus (present) 2.853 0.611-13.331 0.182
Leptin (8.6 ng/ml) 6.195 1.409-27.240 0.016
Resistin (8.8 ng/ml) 3.396 0.823-14.006 0.091
Hyaluronic acid
(76.4 ng/ml)
1.814 0.424-7.766 0.422
-GTP, -glutamyl transpeptidase.
as shown by intraperitoneal glucose and insulin toler-
ance tests [8,9]. In our study, serum levels of AIM were
tended to be correlated with HOMA-IR, although this
correlation was not significant and AIM levels were not
associated with the Matsuda index of whole-body insulin
sensitivity [19]. Simple indices based on fasting levels of
glucose and insulin (e.g. HOMA-IR) assesses hepatic IR
more than peripheral insulin sensitivity [34]. Although it
is unclear whether serum levels of AIM affect hepatic
IR, high serum levels of AIM associated with hepatic
Table 7 Comparison of the clinical characteristics of chronic hepatitis C patients with (A23) or without (A01) severe
hepatic inflammation
A0-A1 A2-A3
n = 32 n = 45
*
Age (years) 51.9 70 20 59.1 76 24 0.039
Sex (male/female) 14/18 17/28 0.598
2
) 23.1 30.1 16.4 23.7 32.2 17.8 0.694
Platelets (10
4
/l) 21.3 41.9 11.1 15.8 39.7 5.4 <0.001
Total cholesterol (mg/dl) 180.9 295 101 163.4 251 84 0.122
Albumin (g/dl) 4.4 5.1 3.3 4.2 4.9 2.9 0.003
ALT (IU/l) 42.2 165 13 80.3 244 14 0.003
-GTP (IU/l) 32.3 114 12 62.8 468 12 0.006
Hemoglobin A1c (%) 5.4 (n = 31) 7.6 4.6 5.4 (n = 44) 7.1 4.7 0.643
Leptin (ng/ml) 7.2 21.8 1 7.8 20.7 1.1 0.247
Adiponectin (ng/ml) 8.9 27.3 1.1 9 26.7 1.7 0.463
Resistin (ng/ml) 8.6 27.6 2.5 8.5 19.7 3 0.687
AIM (g/ml) 1.17 4.56 0.41 1.54 6.44 0.76 0.001
Hyaluronic acid (ng/ml) 58.8 10.0 292.7 123.4 (n = 43) 12.1 636.0 0.001
ALT, alanine aminotransferase; GTP, -glutamyl transpeptidase; HOMA-IR, homeostasis model assessment-insulin resistance; AIM, apoptosis inhibitor of macrophage.
0
1
2
3
4
5
6
7
8
9
0 1 2 3 4 5 6 7
AIM (g/ml)
0
1
2
3
4
5
6
7
8
9
0 5 10 15 20 25 30
Adiponectin (ng/ml)
0
1
2
3
4
5
6
7
8
9
0 5 10 15 20
Leptin (ng/ml)
0
1
2
3
4
5
6
7
8
9
0 2 4 6 8 10 12 14 16 18
Resistin (ng/ml)
H
O
M
A
-
I
R
H
O
M
A
-
I
R
H
O
M
A
-
I
R
H
O
M
A
-
I
R
r = 0.269
P= 0.098
r= -0.337
P= 0.036
r= 0.361
P= 0.024
r= 0.356
P= 0.026
Figure 1 Correlation between serum levels of AIM, adiponectin, leptin, or resistin and HOMA-IR. Resistin and leptin levels were positively
and serum adiponectin levels were negatively correlated with HOMA-IR. There was a tendency towards a positive correlation between serum AIM
levels and HOMA-IR. AIM, apoptosis inhibitor of macrophage; HOMA-IR, homeostasis model assessment-insulin resistance. Correlation coefficients
were calculated by Spearmans rank correlation analysis.
fibrosis potentially connect hepatic fibrosis to IR. Fur-
ther examination in patients with the same stage of fi-
brosis is needed.
In this study, serum levels of leptin were associated
with HOMA-IR and hepatic steatosis, but not hepatic fi-
brosis and inflammation. Previous studies similarly
showed that serum leptin levels are associated with IR
[18] and hepatic steatosis [35]. In contrast, Cua et al.
also reported that serum leptin levels are not associated
with histological findings [18], but Piche et al. showed
an association between serum leptin levels and the se-
verity of hepatic fibrosis [36]. Resistin levels were re-
ported to be inversely associated with hepatic fibrosis
and resistin may stimulate fibrogenesis directly or indir-
ectly through hepatic inflammation [14,16], but our
study indicates that serum levels of resistin are not asso-
ciated with hepatic fibrosis. In addition, Jonsson et al. re-
ported that serum adiponectin levels were correlated
with HOMA-IR and inversely correlated with steatosis
in HCV-infected male subjects [37]. However, Liu et al.
reported that adiponectin levels do not correlate with
histological features such as hepatic steatosis, although
low adiponectin levels are associated with HOMA-IR in
patients with CHC [38]. Thus, prior studies on the role
of the adipocytokines including adiponectin, leptin, and
resistin, in the pathogenesis of histological changes in
the liver and IR in patients with CHC have yielded con-
flicting results [16]. It is noteworthy that an association
between BMI and steatosis has been reported [5,6]. Fur-
ther, more severe steatosis is associated with more rapid
progression of fibrosis [39]. In our study population,
BMI is lower and hepatic steatosis is less severe com-
pared to a previous study [21]. In addition to BMI and
histological findings, many other factors such as study
population and sample size should be carefully consid-
ered when interpreting the data.
There are several limitations to this study. First, there
were no F4 patients among the 77 HCV-infected pa-
tients analyzed in whom ultrasound-guided liver biopsy
was performed. This selection bias was likely due to the
fact that patients with suspected liver cirrhosis usually
do not undergo liver biopsy for histological examination.
In addition, the number of patients with OGTT data
was small (only 39 patients). Further examination using
a large number of patients with OGTT data available, in-
cluding patients with compensated cirrhosis, is needed.
Second, we employed a 5% cut-off for the amount of fat
within the liver; some reproducible histological scales
use the categories of mild (510%), moderate (1130%),
and severe steatosis (>30%) [39]. Itoh et al. also divided
patients into groups with 010% and >10% hepatic stea-
tosis [40]. However, the proportion of patients with 5%
or 11% hepatic steatosis in our study population was
small (18/77 [23.4%] or 3/77 [3.9%], respectively) com-
pared to earlier studies. The reason for this difference in
the distribution of hepatic steatosis severity is unclear,
but there might be regional differences. In addition, the
cut-off of 5% steatosis may not be clinically significant,
and we should keep in mind that factors associated with
steatosis might depend on the cut-off value used to
0
2
4
6
8
10
12
14
16
18
0 1 2 3 4 5 6 7
0
2
4
6
8
10
12
14
16
18
0 5 10 15 20 25 30
0
2
4
6
8
10
12
14
16
18
0 5 10 15 20
0
2
4
6
8
10
12
14
16
18
0 2 4 6 8 10 12 14 16 18
AIM (g/ml) Adiponectin (ng/ml)
Leptin (ng/ml) Resistin (ng/ml)
W
B
I
S
I
W
B
I
S
I
W
B
I
S
I
r= -0.130
P= 0.430
r= 0.321
P= 0.046
r= -0.368
P= 0.021
r= -0.409
P= 0.010
W
B
I
S
I
Figure 2 Correlation between serum levels of AIM, adiponectin, leptin, or resistin and WBISI. Serum AIM levels were not correlated with
WBISI, but serum adiponectin levels were positively and serum resistin and leptin levels were negatively correlated with WBISI. AIM, apoptosis
inhibitor of macrophage; WBISI, whole body insulin sensitivity index [19]. Correlation coefficients were calculated by Spearmans rank
correlation analysis.
define steatosis. Thus, the association between serum
AIM levels and hepatic steatosis should be re-evaluated
in studies with more subjects that include patients with
severe hepatic steatosis. Third, several confounders such
as alcohol consumption, previous interferon treatment,
HCV genotype, and genetic factors including interleukin
28B polymorphism [41], were not considered. The asso-
ciation between examined cytokines and hepatic fibrosis
or steatosis in patients with CHC should be further ex-
amined in large-scale nationwide studies in the future.
Conclusions
Serum AIM levels in CHC patients increased as hepatic fi-
brosis progressed, but serum levels of adipocytokines were
not associated with hepatic fibrosis. In contrast, serum
levels of AIM may not be correlated with IR as assessed
by HOMA-IR, but adipocytokines were associated with IR
and insulin sensitivity, and serum levels of leptin were as-
sociated with hepatic steatosis. These results suggest that
serum AIM levels are not only associated with HCV-
related hepatic fibrosis, but that AIM and adipocytokines
are also possibly associated with pathological changes in
patients with CHC via a different mechanism.
Competing interests
HT holds endowed faculty positions in research for HGF tissue repair and
regenerative medicine and has received funds from Eisai Co., Ltd.
Authors contributions
KM and HU: principal investigator, data collection, subject evaluation and
manuscript preparation. SM, AI, YY and TN: subject evaluation and statistical
analysis. KO and KT: subject recruitment and subject evaluation. KK, TT, AM,
MO, YS, MH and SE: subject recruitment and data collection. HU and HT:
guarantor of the article. All authors read and approved the final manuscript.
Acknowledgments
We thank Ms. Ayaka Hamabe, Ms. Yuko Morinaga, and Ms. Etsuko Horiguchi
for their technical assistance. This work was supported in part by grants from
the Ministry of Education, Culture, Sports, Science and Technology of Japan
to HU (23590981) and HT (23249043), and the Ministry of Health, Labour and
Welfare of Japan to HU.
Author details
1
Digestive and Lifestyle Diseases, Department of Human and Environmental
Sciences, Kagoshima University Graduate School of Medical and Dental
Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan.
2
Miyazaki
Prefectural Industrial Support Foundation, 16500-2 Higashikaminaka,
Sadowara-cho, Miyazaki 880-0303, Japan.
3
Department of Surgery, Nagasaki
University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto,
Nagasaki, 8528501, Japan.
4
Department of HGF Tissue Repair and
Regenerative Medicine, Kagoshima University Graduate School of Medical
and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan.
Received: 16 October 2013 Accepted: 5 February 2014
Published: 13 February 2014
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Cite this article as: Mera et al.: Serum levels of apoptosis inhibitor of
macrophage are associated with hepatic fibrosis in patients with
chronic hepatitis C. BMC Gastroenterology 2014 14:27.
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